The innate immune system senses the invasion of microorganisms by using the family of Toll-like receptors (TLRs), which recognize specific components conserved among microorganisms and initiates a range of host defense mechanisms. The TLRs share sequence homology with the interleukin-1 receptor family in the intracellular Toll-IL-1 receptor domain (TIR domain). Similar cytoplasmic domains allow TLRs to share common signaling pathways with the IL-1 receptor to induce a core set of responses, such as inflammation. However, individual TLRs can also induce immune responses that are specific to a given microbial infection. Dysregulation of these immune responses may leave the host susceptible to infection, lead to lethal systemic inflammation or chronic inflammation such as inflammatory bowel disease. While tremendous effort has been devoted to understanding the mechanisms used by this Toll-IL-1 R superfamily, little is known about the negative regulation of these receptors. Through database searching, we recently discovered a novel TIR-domain containing receptor, the single immunoglobulin IL-1 receptor related molecule (SIGIRR). However, SIGIRR does not activate the pathways and instead negatively modulates TLR-dependent responses. Inflammation is enhanced in SIGIRR-deficient mice, as measured by enhanced chemokine induction after IL-1 injection and a reduced threshold for lethal endotoxin challenge and increased susceptibility for chemically induced inflammatory bowel disease. Cells from these mice show enhanced activation in response to either IL-1 or certain Toll ligands. Finally, biochemical analysis indicates that SIGIRR binds to the Toll-IL-1 R signaling components in a ligand-dependent manner. Based on this data, we hypothesize that SIGIRR functions as a biologically important modulator of Toll-IL-lR signaling, thereby regulating the inflammatory and innate immune responses. To test this hypothesis, we will carry out the following Specific Aims: (1) Elucidate the molecular mechanism by which SIGIRR exerts its inhibitory role in Toll-IL-1 receptor-mediated signaling using ex vivo and in vitro cell culture systems; (2) Determine the impact of SIGIRR on intestinal mucosal immunity using in vivo animal models. Through these studies, we will have a better understanding about how SIGIRR exerts its inhibitory role on the signaling events mediated by IL-1 and Toll ligands, and also about the physiological function of SIGIRR, which should provide insight into the innate immune responses. Specifically, the proposed studies should result in significant advances in the field of innate mucosal immunity and should also help us to determine the potential of SIGIRR as a target for developing anti-inflammatory drugs.